A natural nucleoside is a glycoside comprising a ribose or a deoxyribose and a base (such as adenine, thymine, guanine, cytosine or uracil), and is an important component of DNA and RNA. Artificially synthesized nucleoside analogues are an important class of chemotherapeutic drugs for tumor, and are referred to as antimetabolites. The effect thereof is mainly achieved by affecting enzymatic system in tumor cells, thereby inhibiting the synthesis of DNA and RNA. According to statistics from WHO, cancer is one of the leading causes of death worldwide. Moreover, drug resistance in cancer cells is ubiquitous, and it is urgently needed to develop new anti-cancer drugs for human health. As such, it is an arduous task in the pharmaceutical industry to develop safe and reliable anti-cancer drugs from various perspectives. Treatment employing an organ specific nucleoside prodrug represents one of the most promising therapeutic methods.
Nucleoside drugs, such as gemcitabine, azacitidine, decitabine, cytarabine, fludarabine, cladribine, 6-azauridine, tiazofurine and atromide, etc., have been widely used for the treatment of various cancers. There are many nucleoside drugs that are currently at different stages of clinical development.
Gemcitabine is a pyrimidine nucleoside analogue developed by Eli Lilly and Company in the US, and is an important nucleoside-based anticancer drug as a first-line therapeutic agent for advanced pancreatic cancer, advanced non-small cell lung cancer, localized or metastatic bladder cancer and metastatic breast cancer. It has a broad spectrum of anti-tumor activity, and is effective for a variety of additional solid tumors. Gemcitabine generally needs to be administered in combination with paclitaxel, cisplatin, and/or carboplatin. Gemcitabine has poor cell permeability, low bioavailability, and a short half-life in cells (between 32˜94 min), and thus must be continuously intravenously administered at a high dose (with a recommended dose of 1000 mg/m2), so as to maintain its effective blood drug concentration and toxicity to cancer cells. The dose-limiting toxicity induced by the high dose of gemcitabine employed affects clinical efficacy, and results in a series of side effects and safety issues, such as leukopenia, transaminase abnormalities, proteinuria, as well as nausea and vomiting, etc. In addition, gemcitabine has a number of shortcomings, including lack of tissue specificity which leads to high systemic toxic effects; rapid metabolism and a short plasma half-life; drug resistance in tumors; poor effects achieved through oral administration, common requirement of administration through intravenous injection, a high dosage and severe side effects; poor efficacy achieved when the drug is administered alone, and necessity of co-administration with another anti-cancer drug; etc.
Gemcitabine has poor oral bioavailability, and thus generally needs to be administrated via intravenous injection. The poor oral bioavailability is a result of first-pass metabolism (see Shipley L A., et al., “Metabolism and disposition of gemcitabine, and oncolytic deoxycytidine analog, in mice, rats, and dogs”. Drug Metabolism & Disposition. 20(6):849-55, 1992). In addition, when dosed orally, gemcitabine is implicated in causing adverse dose-limiting intestinal lesions characterized by moderate-to-marked loss of mucosal epithelium (atrophic enteropathy) throughout the entire length of the intestinal tract in mice given a single oral (gavage) gemcitabine dose of 167, 333, or 500 mg/kg (see Horton N D et al., “Toxicity of single-dose oral gemcitabine in mice”, American Association for Cancer Research, Poster Presentation, Orlando, Fla., Mar. 27-31, 2004). In a previous study performed on mice, no death or gastrointestinal toxicity was observed when a significant dose was administered intravenously.
Moreover, gemcitabine, like other nucleoside drugs, is a hydrophilic compound, and thus cannot go through cellular membranes into cells via passive diffusion, but needs a specific transport protein to be delivered into tumor cells. Alteration in the nucleoside transport activity has been considered as an important cause of resistance to gemcitabine. Human equilibrative nucleoside transporter 1 (hENT1) is an important transport protein currently identified for the transportation of gemcitabine into tumor cells. As reduction of intracellular drug accumulation would likely result in decreased sensitivity to gemcitabine, scientists at Clavis Pharma, Norway, have synthesized a 5′-elaidic acid ester derivative of gemcitabine, CP-4126, which has significantly improved lipophilicity than that of gemcitabine. Studies show that CP-4126 can get into tumor cells independent of hENT1 transporter, and thus is expected to exhibit a better anti-tumor effect in tumor patients with a low expression of hENT1.
4′-thionucleoside refers to a nucleoside analogue with the oxygen atom in the furanose ring replaced by a sulfur atom. The synthetic route for 4′-thionucleosides is long and difficult, which greatly limits the study of such compounds. U.S. Pat. No. 6,147,058 discloses a 4′-thionucleoside compound which exhibit inhibitory activity in a colon cancer model in nude mice. This compound is shown to have a better effect in inhibiting tumor growth than that of gemcitabine (Cancer Let. 1999, 144, 177-182; Int. J. Cancer, 2005, 114, 1002-1009). U.S. Pat. No. 5,128,458 discloses a 2′,3′-dideoxy-4′-thioribonucleotides with good effects in the treatment of both a viral infectious disease (such as HIV, hepatitis B or C) and an abnormal cell proliferative disease.
Although the 4′-thionucleoside compound has a better effect in inhibiting tumor growth, it also possesses similar shortcomings to those of gemcitabine, such as low oral bioavailability, fast metabolism, multiple adverse effects and drug resistance, etc.
Resistance to 4′-thionucleoside drugs is a main reason for the short survival period of a patient. The major causes for the development of resistance include: 1) lack of corresponding transporter proteins on the surface of tumor cells, which prevents nucleoside drugs from efficiently passing through cellular membranes; 2) low efficiency of the conversion from the drug to the active species as a triphosphate; and 3) metabolism from the drug to an inactive species in the presence of an enzyme.
Since 4′-thionucleoside drug can be quickly metabolized to an inactive species and lose activity, no 4′-thionucleoside drug is available for the treatment of cancers such as liver cancer to date.
So far, problems encountered in the development of 4′-thionucleoside drugs make them difficult to be approved by authorities. A prodrug approach has been employed to overcome such problems. Now a lot of pharmaceutical companies are still working in developing methods for treating cancers by using other prodrugs (see G. Xu, H. L. McLeod, Clin. Cancer Res., 2001, 7, 3314-3324; M. Rooseboom, J. N. M. Commandeur, N. P. E. Vermeulen, Pharmacol. Rev., 2004, 56, 53-102; W. D. Wu, J. Sigmond, G. J. Peters, R. F. Borch, J. Med. Chem. 2007, 50, 3743-3746).
Upon entry into a body, a nucleoside drug would firstly be phosphorylated to form an active metabolite, monophosphate, through the catalysis of a corresponding kinase, and the monophosphate is then converted to a triphosphate. Monophosphorylation of a nucleoside drug is often a rate-limiting step in the metabolism of the drug. Kinases catalyzing the monophosphorylation of a nucleoside in human bodies (thymidine kinase (TK), deoxycytidine kinase (dCK), deoxyguanosine kinase (dGK) and adenosine kinase (AK)) have a limited affinity to nucleosides, and the kinase activity is liable to be inhibited by nucleotide monophosphate (NA-MP). These both limit the in vivo activation of nucleoside drugs, and affect the exhibition of drug activity. To address this issue, researchers have attempted to modify nucleoside drugs through phosphorylation, so as to obtain corresponding phosphates or phosphamide (ChemMedChem, 2009, 4, 1779-1791).
However, in development of a drug through modification, it is difficult to determine whether the modified drug can successfully release the parent drug after entering the body, since the parent drug is different from case to case, and the modified drug often has reduced or no efficacy, or result in new side effects. As such, in years of research, 4′-thionucleoside compounds currently available still have drugability issues, which are difficult to overcome. Today, after gemcitabine is on the market for many years, there is still no 4′-thionucleoside compound approved for clinical application.